Etiology and treatment of pneumonia

Background. Lower respiratory tract infections are a common cause of morbidity among children. Among these infections pneumonia is the most serious illness and can be difficult to diagnose. The etiology of pneumonia is still partly unknown, primarily because of difficulty in obtaining adequate samples and lack of reliable diagnostic methods. Etiology of pneumonia. Streptococcus pneumoniae is recognized as an important cause of pediatric pneumonia regardless of age in both the inpatient and outpatient setting. In developed countries S. pneumoniae probably accounts for 25 to 30% of cases of pediatric community‐acquired pneumonia. Viruses (mostly respiratory syncytial virus) are responsible for ˜20% of cases, and Chlamydia pneumoniae and Mycoplasma pneumoniae occur commonly in older children. Future challenges. Despite the effectiveness of antimicrobial therapy, the emergence of resistant bacterial pathogens has resulted in increased interest in developing more effective vaccines. If conjugate pneumococcal vaccines prove effective at eradicating carriage of pneumococci in the nasopharynx, immunization may be an important tool against the spread of pneumococcal disease. Future challenges include implementation of effective intervention strategies, production of simple diagnostic tools and development of effective vaccines.


INTRODUCTION
Lower respiratory tract infections are a common cause of mortality in developing countries 1, 2 and represent a major source of morbidity among children worldwide. 3 Although the overall incidence of acute respiratory infections is similar in developed and developing countries, there are marked differences in the proportions of patients with specific infections. 4 The incidence of pneumonia in the developing world is up to 10 times higher than that in developed countries such as the United States (Table 1). Because lower respiratory tract infections can be associated with severe morbidity, such infections place an enormous burden, both economically and as a public health issue, on the entire health care system. 5 Factors such as the age of the patient, nutritional status and underlying disease have a major impact on mortality, morbidity and microbial etiology associated with lower respiratory tract infections. 6 At present the epidemiologic pattern of pneumonia is also being altered by changes in patient characteristics, increased immunosuppression and changes in medical practice. 1 There is also an increasing level of resistance to antimicrobial agents by common pathogenic organisms such as Streptococcus pneumoniae. For these reasons knowledge of the etiologic agents in different patient populations is critical for both the development of vaccines and recommendations regarding treatment. 7

ETIOLOGY OF PNEUMONIA
Identifying the etiologic agent(s) responsible for pneumonia remains a challenge, primarily because of difficulty in obtaining adequate samples for culture and in differentiating infection from colonization and lack of reliable diagnostic methods. 8 -10 Although several factors such as age, underlying disease and environment have a substantial influence on the microbial etiology of pneumonia, 6 S. pneumoniae continues to be an important bacterial cause of pneumonia, especially in infants and young children. 11 More recently Chlamydia pneumoniae and Mycoplasma pneumoniae have been recognized as pathogens responsible for mild to severe lower respiratory tract infections, 11 particularly in children older than 4 to 5 years. In younger patients pneumonia is mostly caused by respiratory viruses. 12 Bacteria that were previously considered nonpathogenic for the respiratory tract such as nontypable Haemophilus influenzae and Moraxella catarrhalis have occasionally been implicated in lower respiratory tract infections. 11 Enterobacteriaceae and Staphylococcus aureus can cause pneumonia in immunocompromised patients. Legionella spp. can also cause sporadic as well as epidemic disease of the lower respiratory tract, although this organism is seen most frequently in adults rather than children.
Pediatric community-acquired pneumonia. A large number of studies have addressed the etiology of pneumonia in adults, but much less evidence is available on the etiology of pneumonia in children. Recently, however, several large prospective studies have investigated the cause of pediatric community-acquired pneumonia (CAP) in European and North American settings using serology alone or serology combined with culture and PCR to define etiology. 12,13 A population-based study of Finnish children (Ͻ15 years of age) with CAP found serologic evidence (using assays for antibody response to three pneumococcal antigens and for specific pneumococcal immunocomplexes and conventional antibody tests) of a microbial etiology in 66% of pneumonia patients. 13 Evidence of bacterial infection was found in 51% of cases and viral infection in 25% of cases. The most frequently found bacterial causes were S. pneumoniae (28%) and M. pneumoniae (22%) (Fig. 1). The total number of Chlamydia spp. infections was 14%, of which 68% were caused by C. pneumoniae (10% overall). In addition, nontypable H. influenzae was identified in 6% and Moraxella catarrhalis in 3% of children. The most common viral agent was respiratory syncytial virus (RSV), which accounted for 21% of cases. Other viruses together accounted for only 4% of cases, among them adenovirus and parainfluenzae viruses.
Serologic evidence of more than one etiologic agent was also found in 25% of patients; these consisted of mixed bacterial infection in 16%, mixed viral-bacterial infection in 10% and mixed viral infection in 1% of cases. 13 The most frequent combinations were S. pneumoniae with RSV or M. pneumoniae. In general the etiology of pneumonia varied according to age (Table  2). Although there were no significant differences in S. pneumoniae etiology in younger and older children (range, 24 to 36%) as determined by antibody and immune complexes, the occurrence of M. pneumoniae and C. pneumoniae infections increased with age (51 and 35% of cases, respectively, in children Ն10 years).
In contrast viral infections, especially RSV infections, were most common in children Ͻ5 years of age. Altogether these results indicate that S. pneumoniae is a common etiologic agent in CAP in children of all ages, and pneumococci are often associated with viral infections (mostly in younger children) and mycoplasmal and chlamydial infections (usually in older children).
Similar results have been reported in the United States. 12 Using culture, PCR and serology, Wubbel et al. 12 identified etiologic agents in 43% of ambulatory pediatric patients (6 months to 16 years) with CAP presenting to an emergency medical center in Texas. This study, which also compared antibiotic therapy, attributed bacterial infection to S. pneumoniae in 27% of patients, followed by M. pneumoniae in 7% and C. pneumoniae in 6%. Eleven percent of children had serologic evidence indicating prior exposure to C. pneumoniae. The percentage with acute or prior Chlamydia infection increased with age (5% at 0 to 2 years and 43% at Ͼ9 years of age). In addition 20% of patients were positive for viral disease (mostly RSV). Of the patients with serologic evidence of acute pneumococcal infection, 40% had coinfection with a virus, C. pneumoniae or M. pneumoniae. The evidence of pneumococcal infection in 27% of patients in this study is nearly identical with the 28% of children reported in the Finnish study. Again, in accordance with the Finnish results, Wubbel et al. 12 found that S. pneumoniae was an important cause of CAP in children across all age groups. Moreover despite different settings and popu-   lations, both studies confirmed that the proportion of viral cases decreases and the proportion of Mycoplasma and/or Chlamydia infections increases in relation to age. Serologic studies for diagnosis of pneumococcal infections are investigational. Thus interpretation of results must be guarded with respect to determination of incidence rates of pneumococcal diseases in children.
Two large prospective studies further defined the association between Mycoplasma and Chlamydia infections in children with community-acquired pneumonia. 14,15 In one multicenter study pretreatment culture, PCR and serology was performed for C. pneumoniae and M. pneumoniae in patients (6 months to 16 years) presenting to geographically diverse centers in the United States. 15 Evidence of infection was identified in 46% of patients by pretreatment culture or serology, with 15% of patients having C. pneumoniae and 30% having M. pneumoniae infection. The trend toward lower rates of infection with C. pneumoniae and M. pneumoniae in younger children was also observed in this study (Fig. 2). 15 In patients Յ5 years of age 15% of cases were associated with M. pneumoniae and 9% were associated with C. pneumoniae vs. 42 and 20%, respectively, in patients Ͼ5 years of age.
Using similar diagnostic techniques (culture, PCR and serology), C. pneumoniae was documented in 28% and M. pneumoniae in 27% of patients (3 to 12 years of age). 14 Serologic confirmation of infection was observed in 23 and 53% of patients with documented C. pneumoniae and M. pneumoniae infection, respectively. Consistent with the findings of other studies, younger children had fewer infections caused by C. pneumoniae and M. pneumoniae.
Etiology of acute lower respiratory tract infection in hospitalized children. To investigate the etiology of acute lower respiratory tract infection in children (mean, 1.75 years of age) requiring hospitalization, Nohynek et al. 7 used both conventional microbiologic methods and a range of serologic methods (bacterial antibody assays and detection of viral and bacterial antigens and nucleic acid). The study established an etiologic diagnosis in 70% of cases. Twentyfive percent of episodes were found to be associated with a bacterial agent and 25% with a viral agent; in 20% of episodes a mixed infection was diagnosed. Among the bacterial agents nontypable H. influenzae and S. pneumoniae were the most common organisms (17 and 16% of all patients, respectively). Moraxella catarrhalis was found in 7% and M. pneumoniae in 9% of the cases. Of the viral agents RSV was encountered in 28% of patients. The remaining viral agents were adenovirus, influenzae A or B and parainfluenzae type 1.
Although this study involved only hospitalized patients, the findings support the notion that bacterial etiologies of pneumonia increase with age, whereas viral diseases decrease (Fig. 3). 7 For example S. pneumoniae was seen in all ages and M. pneumoniae in all ages except infants, although the proportional roles of both of these etiologic agents increased with age. With regard to viruses RSV and adenovirus were more common in infants and young children.

MANAGEMENT OF PNEUMONIA
For the management of pneumonia, it is important to define the likely etiology and grade the severity of the infection. 1 Ideally treatment should be directed against the identified pathogen, but this is impractical in pediatric patients. 2 In the past, however, there have been only fragmentary data on culture, serology and PCR results in pediatric pneumonia in relation to clinical course and antimicrobial therapy. 12 More recently three studies, which defined the etiology of CAP in children, also compared the efficacy of newer macrolides vs. conventional therapy using some or all of these diagnostic methods. 12,14,15 Taken in aggregate the evidence from these comparative studies indicates that treatment with traditional antimicrobials, such as amoxicillin alone or amoxicillin/clavulanate or erythromycin, or with newer macrolides, including azithromycin and clarithromycin, produce satisfactory rates of clinical cure and are similarly effective for the treatment of CAP in children.
Treatment of antimicrobial-resistant pneumonia. Despite progress in the management of pneumonia in children, the emergence of multidrug-resistant pathogens continues to pose challenges for the clinician. In particular drug-resistant S. pneumoniae is a growing concern because of the importance of this pathogen in infections of the respiratory tract in infants and children. 16 Recently the effects of increased antimicrobial resistance on the management of pediatric pneumonia were assessed in a US-based, multicenter, retrospective study that compared the treatment and outcome of patients with pneumonia attributed to penicillin-susceptible or -nonsusceptible S. pneumoniae. 17 Of the 257 isolates obtained in this study, 9% were penicillin-intermediate and 6% were resistant to penicillin. 17 In addition 3% were intermediate to ceftriaxone and 2% were resistant to ceftriaxone. The types of antimicrobial regimens were highly variable in this retrospective analysis; however, 80% of patients treated as outpatients and 48% of inpatients received a parenteral second or third generation cephalosporin followed by a course of an oral antimicrobial agent. Overall the clinical presentation and outcome of therapy did not differ significantly between patients with penicillin-susceptible vs. those with nonsusceptible isolates of S. pneumoniae. However, it is likely that a majority of patients from whom pneumococci were recovered from blood or pleural fluid cultures received initial treatment with intravenous antibiotics. This route would result in excellent eradication of even the most resistant pneumococcus, whereas oral antibiotic therapy may not be as effective.
A prospective study conducted in South Africa further defined the optimal therapy and clinical response in penicillin-resistant bacteremic pneumococcal infections in children. 18 Approximately three-fourths of the children in this study had pneumococcal pneumonia. Patients were treated with a number of different daily antimicrobial regimens, including oral beta-lactam therapy or intravenous penicillin G (100 000 units/kg), ampicillin (100 mg/kg), amoxicillin (40 to 60 mg/kg), cefuroxime, cefotaxime or ceftriaxone (all 80 to 100 mg/kg), or vancomycin (40 mg/kg). After 48 h of therapy 64% of penicillin-susceptible infections showed improvement compared with 60% of penicillin-resistant infections. By Day 7 of therapy 93% of children with penicillin-susceptible pneumococcal pneumonia treated with ampicillin or an equivalent beta-lactam had improved compared with 88% with resistant infections.
Role of vaccines in prevention of pneumonia. In spite of the effectiveness of standard antimicrobial therapy, effective vaccination against pneumococcal infections is desirable not only because of the continued emergence of antibiotic-resistant strains but also because prevention of pneumococcal disease is the ultimate goal. 19 The existing capsular polysaccharide vaccine is neither immunogenic nor protective in young children, 19 and it is not recommended for use in those younger than 2 years. 20 Given the immunogenic nature of S. pneumoniae proteins, however, these molecules are currently being investigated as potential vaccine candidates. 19,20 If conjugate pneumococcal vaccines also prove to eradicate carriage, immunization may be an important weapon against the spread of pneumococcal infection. 21 Nevertheless such vaccines will represent only a partial solution to the management of pediatric pneumonia because of the complex and varied etiology of the disease.
To date, clinical trials of first generation pneumococcal conjugate vaccines have shown that covalent coupling of pneumococcal capsular polysaccharides to protein carriers improves the immunogenicity of the polysaccharides. 19 Most recently the efficacy of a pneumococcal conjugate vaccine was assessed in a large, randomized, double blinded, controlled clinical trial in a multiethnic pediatric population in Northern California. 22 Primary immunization occurred at 2, 4 and 6 months of life follwed by a booster dose at 12 months. Preliminary results indicate that the vaccine is effective in reducing the incidence of pneumonia caused by S. pneumoniae with capsular serotypes covered by the vaccine (4, 6B, 9V, 14, 18C, 19F, 23F).

CONCLUSION
The causes of acute lower respiratory tract infections, including pneumonia, are still incompletely defined, primarily because of the difficulty in obtaining adequate samples for testing and the lack of reliable diagnostic methods. 8,10 This is an important shortcoming, because knowledge of etiologic agents in different patient populations and settings is crucial for both the development of vaccines and recommendations regarding treatment. 7 In recent years, however, newer diagnostic methods, such as serology and PCR testing, have complemented the use of blood and pleural fluid cultures to assess the etiology of pneumonia. In the future immunization with conjugate pneumococcal vaccines may become an important means of reducing the incidence of pneumococcal infections in children. Although much progress has been made in defining the etiology and treatment strategies for pediatric pneumonia, research is still needed to determine the spectrum of organisms involved and to delineate the pathogenesis of infection. The challenge for the future is to evaluate and implement effective intervention strategies, produce simple and inexpensive diagnostic tools and develop vaccines that will be effective in the target populations.